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Abstract:

A removable intraoral device is useful for longitudinal in vivo biofilm
research. The device is adapted to allow it to be retained in the oral
cavity long enough for biofilm to form and to affect the oral mucosa. The
device is readily removable to facilitate longitudinal observations. The
device is biostable. The device does not interfere with the animal's
daily activities such as eating and drinking. The device can be
fabricated and maintained at low cost.

Claims:

1. An intraoral device for a rodent; said device comprising a fixed part
and a removable part; wherein: (a) said fixed part has a shape that is
complementary to the rodent's anterior palate, and said fixed part is
held in place adjacent the posterior palate by fixed attachment to the
rodent's upper cheek teeth; (b) said removable part is magnetically held
in place adjacent said fixed part; and at least a portion of the surface
of said removable part comprises a dental restorative material, wherein a
surface of the dental restorative material contacts the rodent's
intraoral tissue; (c) said fixed part comprises a permanent ferromagnet
or a ferromagnetic material; and said removable part comprises a
permanent ferromagnet or a ferromagnetic material; wherein at least one
of said fixed part and said removable part comprises a permanent
ferromagnet; wherein said fixed and removable parts will magnetically
attract one another with sufficient force to hold said removable part in
place, adjacent said fixed part within the rodent's mouth, for an
extended period of time without being dislodged by the normal activities
of the rodent; but wherein said removable device may easily be removed
from the rodent's mouth by a human when desired, by applying a mechanical
force to the removable part sufficient to overcome the magnetic force
between said fixed and removable parts.

2. A device as in claim 1, wherein said fixed part is held in place by
fixed attachment to the rodent's upper cheek teeth with one or more
orthodontic ligature wires, wherein each said wire is shaped into a loop
on one end.

Description:

[0001] The benefit of the May 27, 2010 filing date of U.S. provisional
patent application Ser. No. 61/348,816 is claimed under 35 U.S.C.
§119(e). The entire disclosure of the provisional application is
incorporated by reference.

[0003] This invention pertains to a convenient, removable intraoral device
for use in rodents. It is useful, for example, in studies of materials
that are used in prosthodontic devices, in studies of the biofilms that
adhere to such devices, and in methods for treating oral diseases related
to those biofilms.

[0004] A "biofilm" is a community of microbial cells that are attached to
a substrate, to an interface, or to each other, in which the cells are
embedded in a matrix of extracellular polymers secreted by the cells
themselves. In the oral cavity, biofilms play a major role in several
infectious diseases, including dental caries, periodontitis, and
prosthesis-associated infections such as denture stomatitis. Denture
stomatitis is a common oral mucosal disease that is associated with
Candida albicans, appearing in 27-50% of denture-wearers. Biofilms can
cause persistent infections that are often resistant to conventional
antimicrobial agents. Further studies of Candida biofilms could yield
significant improvements in the prevention and treatment of denture
stomatitis. There is an unfilled need for improved animal models to study
biofilms in the oral cavity, particularly biofilms that form upon or in
association with prosthodontic devices.

[0005] A convenient intraoral device that is adapted for use in an animal
model would be highly useful to researchers studying biofilms, such as
Candida biofilms. Such a device could allow researchers to better observe
the pathogenesis of infection, interactions between the biofilm and the
prosthesis, and interactions between the biofilm and host responses
(e.g., from oral mucosa). These interactions are simulated poorly by in
vitro models. There is an unfilled need for an intraoral device with the
following characteristics: 1) The device should be adapted to be retained
in the oral cavity long enough for a biofilm to form and to affect the
oral mucosa. 2) The device should be readily removable to facilitate
longitudinal observations. 3) The device should be biostable. 4) The
device should not interfere with the animal's daily activities such as
eating and drinking. 5) The device should be easy to fabricate at low
cost. To our knowledge, there is no previously reported device that
satisfies all these criteria.

[0007] There is an unfilled need for a removable intraoral device for
rodents, particularly rats. The usual mechanisms for retaining removable
prostheses in the human oral cavity do not work well in rodents, due to
the very different morphologies of the oral cavity, jaws, and teeth. A
rat will not voluntarily tolerate a foreign object in its mouth. The size
of the rat's oral cavity is too small to use conventional clasps or
attachments for intraoral devices such as might be used in humans. The
jaw bone is too thin to anchor a dental implant in the bone. In larger
animals, dental devices that are more similar to those used for humans
could perhaps be effective, but the cost of research generally increases
substantially for larger animals.

[0008] We have discovered a novel, removable intraoral device for use in
rodents that is adapted to be retained in the oral cavity long enough for
a biofilm to form and to affect the oral mucosa. The novel device is
readily removable to facilitate longitudinal observations. The novel
device is biostable. The novel device does not interfere with the
animal's daily activities such as eating and drinking. The novel device
can be fabricated and maintained at low cost. The novel device is useful
for prosthodontic studies generally, and in particular it is well-suited
for biofilm research.

[0009] The novel device may be used for research into many areas involving
prosthodontic materials, biofilms, or prosthetic-associated infectious
diseases. Examples include the pathogenesis and treatment of denture
stomatitis, the testing of antimicrobial denture materials, the testing
of drug delivery systems, and so forth.

[0010] The novel device contains a fixed part, anchored by orthodontic
wire between the rodent's teeth, for example with acrylic resin; and a
removable part, which may adhere to the fixed part with magnets. The
device is small, simple, and inexpensive. The removable part may be
removed and replaced with ease, not requiring any special tools. The
anterior portion of the palate is accessible for studying the interaction
between the removable part and the oral mucosa. The posterior portion of
the palate is covered by the fixed part of the device. Corrosion of the
magnets was a concern in an early prototype, but we found that coating
the magnets, for example with a gypsum hardener, protected the magnets
from corrosion for at least two months and likely longer. Even with the
earlier, non-gypsum hardener-coated prototype, the minor corrosion did
not appear to affect retention of the removable part, nor to affect
adjacent soft tissue. The device did not appear to interfere with the
rat's normal daily activities, such as eating and drinking. Nor did it
appear to affect the rats' body mass.

[0011] The novel device is durable. All devices tested to date have
remained in place in the rats' mouths for at least two months, a
sufficient time for disease to development and for the study of biofilms.
We have tested over 50 of the novel devices. In a few instances, after
times longer than two months, the fixed part has loosened as the acrylic
resin on the occlusal surface eroded due to constant wear from the
opposing teeth. However, those devices were easily repaired by adding new
acrylic resin to the broken area under anesthesia. It was not necessary
to remove the old acrylic; the new acrylic was simply added atop the old.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 depicts schematically one embodiment of the fixed part of
the novel device.

[0013]FIG. 2 depicts schematically one embodiment of the removable part
of the novel device.

[0014]FIG. 3 depicts schematically one embodiment of the novel device
positioned within a rat's mouth.

[0015] Description of prototype device and method of fabrication and
installation. FIGS. 1-3 depict schematically a prototype device that has
been constructed in accordance with the present invention. FIG. 1 depicts
a cast model 1 of a rats maxilla, the fixed portion 2 of the novel
device, containing two magnets 3. FIG. 2 depicts the removable portion 4
of the device, containing metal bar 5. FIG. 3 depicts an intraoral view
of the prototype device in rat's mouth, showing both the fixed portion 2
and the removable portion 4.

[0016] (1) Male Wistar rats (retired breeders) were used in fabricating
and installing prototype devices in accordance with the present
invention. (2) Each rat was weighed, and anesthesia was administered in
accordance with standard protocols. (3) The rat was placed in a supine
position, and the mouth was opened.

[0017] (4) A piece 5 mm wide by 50 mm long was cut from a wooden tongue
depressor. One end of the cut wood was coated on both sides with a vinyl
polysiloxane (VPS) adhesive (Tray Adhesive; Dentsply Caulk, Milford,
Del.), which was then air-dried. (5) A light-body VPS impression material
(Aquasil Ultra LV; Dentsply Caulk) was injected directly onto the palate
and onto all maxillary cheek teeth using a manual, gun-type dispenser
(Cartridge Dispensing Gun; Dentsply Caulk), an auto mix tip (Mix Tips;
Dentsply Caulk), and an intraoral tip (Intra-Oral Tips; Dentsply Caulk).
The adhesive-coated end of the cut wood was gently placed on top of the
impression material immediately after the first injection, and the end of
the tongue depressor was then covered with a second injection of VPS. The
VPS was then allowed to polymerize in place.

[0018] (6) The impression was then gently removed from the rat's mouth,
and used to form a counterpart in type III dental stone (Quickstone; Whip
Mix Corp, Louisville, Ky.). After setting, the stone cast was separated
from the impression and trimmed. (7) An acrylic separating agent (Al-Cote
Separating Agent; Dentsply Caulk) was coated onto the cast surface. A 2
mm wax dam (Sculpturing Wax Blue Transparent; Renfert GmbH, Hilzingen,
Germany) was formed across the mesial aspects of the maxillary right and
left first cheek teeth, in order to separate the area for the fixed part
from that for the removable part.

[0019] (8) A stainless steel surgical blade (No. 25; Miltex, Inc, York,
Pa.) was cut into a metal bar 3 mm wide and 12 mm long, with two notches
at one end. The steel blade was cut with a carborundum separating disc
(Ultraflex; Keystone Industries, Cherry Hill, N.J.). (9) Two magnets
(D21B-N52, Nd--Fe--B, disk shape, diameter 1/8 inch, thickness 1/16 inch;
K&J Magnetics, Inc, Jamison, Pa.) were coated with a gypsum surface
hardener to inhibit corrosion. The two magnets were positioned in the
middle of the cast stone palate, and the metal bar was attached to the
magnets. The bar was temporarily attached to the cast with wax.

[0020] (10) A thin mix of autopolymerizing acrylic resin (Jet Tooth Shade
Acrylic; Lang Dental, Wheeling, Ill.) was poured onto the cast to cover
the palate and the magnets, but not the metal bar. After the polymer had
cured, the metal bar was detached from the magnets, and the wax was
cleaned both from the cast and from the metal bar. The bar was then
replaced in the same position on the magnets.

[0021] (11) Another batch of the autopolymerizing acrylic resin was
prepared and applied to cover the notch side of the metal bar, without
reaching the fixed portion. After polymerization, both the fixed and
removable parts were removed (12) Using an acrylic bur (Long Cross Cut
Fissure; Brasseler USA, Savannah, Ga.), notches were cut on both the left
and right sides of the removable part. The fixed and removable parts were
trimmed.

[0022] (13) An orthodontic ligature wire (Item number 4920-110, 0.25 mm
diameter; Masel, Bristol, Pa.) was cut into 2 pieces, each piece 15 mm
long. A loop was formed on one end of each of the pieces of wire, so that
the overall length of each piece was 7 mm. By using this loop
configuration, one may save considerable time over an alternative
procedure such as tying a knot. (The use of an orthodontic wire loop in
prosthodontic devices is not a standard practice.)

[0023] (14) The rat was again anesthetized and placed in a supine position
with the mouth open. Ligature wires were inserted from the buccal side in
both the right and left interproximal spaces, between the first and
second cheek teeth. The extruded wires were bent from the palatal side
over the occlusal surface. (15) The assembly of fixed and removable parts
was placed in the rat's mouth and the fit was checked. Using a
"salt-and-pepper" technique, small increments of the autopolymerizing
acrylic resin were applied to the cheek teeth with a dental brush (Red
Sable Brush, #2; Keystone Dental, Inc, Burlington, Mass.), to bond the
cheek teeth to the fixed part of the device. Care was taken to cover the
wire and all occlusal surfaces with the acrylic resin. The acrylic resin
was not allowed to contact the removable part. (16) After the acrylic
resin had polymerized, we checked the security of the fixed part, and we
checked the removability of the removable part.

[0024] Preliminary Results. A removable intraoral device as described
above was installed into the mouth of each of a group of rats under
anesthesia. The rats were weaned from a pellet diet to a gel diet to keep
food debris from collecting between the denture and the palate. Candida
was then inoculated as a paste onto the palate of anesthetized rats.
After 28 days, scanning electron microscopy (SEM) showed biofilm
formation on the device, but not yet on the palate. After 42 days, SEM
showed biofilm formation on both the device and the palate. After 42
days, clinical manifestations of biofilm-related infection were observed
on the palate, including pin-point hyperemia, diffuse erythema, and
papillary hyperplasia. A control rat that was not fitted with the device,
but that had been inoculated with Candida onto the palate, showed no
signs of biofilm-related infection, either clinically or microscopically.
Likewise, a rat with a denture installed, but without inoculation, had no
evidence of Candida colonization on either the palate or the denture, and
showed no signs of disease.

[0025] The complete disclosures of all references cited in this
specification are hereby incorporated by reference, as is the complete
disclosure of the priority application Ser. No. 61/348,816, filed May 27,
2010. Also incorporated by reference is the complete disclosure of the
following publications by the inventors and colleagues: H. Lee et al.
Fabrication of a multi-applicable removable intraoral denture system for
rodent research. J. Oral Rehab. (e-pub online ahead of print, Feb. 17,
2011); H. Lee et al., "Establishment of a Contemporary Rat Model of
Candida-Associated Denture Stomatitis to Evaluate the Role of Biofilm in
Disease," Abstract, 10th ASM Conference on Candida and Candidiasis; 2nd
ASM Conference on Dimorphic Fungal Pathogens, Miami, Fla. (Mar. 22-26,
2010). In the event of an otherwise irreconcilable conflict, however, the
present specification shall control.